The human retina is a thin layer of neural tissue at the back of the eye that transforms light into electrical signals for the brain. The retina can be divided into distinct regions related to their visual function. These distinct regions are: (i) the posterior pole, where the majority of photoreceptor cells (responsible for central, high acuity color vision) lie; and (ii) the periphery, which includes everything outside the posterior pole. In particular, the posterior pole includes a non-photosensitive structure known as the optic nerve and the macula. Within the center of the macula is a region known as the fovea, which is responsible for nearly all of our high acuity color vision.
The process of diagnosing an inherited retinal disease typically involves recording demographic information about the patient, documenting their ocular and medical history including the age of onset and reported symptoms, evaluating the family history to determine if there is specific genetic mode of transmission that can be distinguished, and performing a clinical evaluation. The clinical evaluation often includes diagnostic testing with a best corrected visual acuity (BCVA) measurement, electroretinography (ERG) measurement, a Goldmann visual field (GVF) measurement, and interpretation of retinal imaging (e.g., optical coherence tomography, fundus autofluorescence, and fluorescein angiography).
Although the diagnostic process is simple in principle, the task is, in practice, an art. A clinician bases a diagnosis on previous experience and knowledge of the existing literature, and, as a result, only a handful of specialists in the United States can effectively diagnose and manage patients with inherited retinal conditions. Moreover, several factors complicate the diagnostic process, because inherited retinal conditions are clinically and genetically heterogeneous. First, variability can arise in the clinical presentation of patients with the same condition. Second, findings between conditions can have considerable overlap, and a clinician must understand which findings are more useful in making the correct diagnosis. Still further, even if the clinician does have a clear understanding of clinical findings and the likely diagnosis, the clinician must be able to use available information to order appropriate genetic testing for molecular confirmation of the diagnosis. This requires additional proficiency in the complicated field of genetics, because multiple genes can cause the same condition.
Confirming a clinical diagnosis with genetic testing is important because such a confirmation can play a vital role in the management and preservation of vision in patients by aiding in the determination of appropriate therapeutic interventions. Currently, however, cost conscious health management organizations demand that clinicians employ the most cost-effective means for diagnosing a patient's condition. The cost of screening a single gene can be anywhere from several hundred to several thousands of dollars. It can, therefore, be cost prohibitive to pursue genetic testing for all genes associated with a particular condition. Also, screening large numbers of genes introduces logistical complexity in the process of diagnosis. Even when multiple genes can be tested at the same time, as in a panel of genes or with whole genome sequencing, determining causative mutations from polymorphisms can be guided by an assessment of the patient's phenotype.